Analysis of 10,478 cancer genomes identifies candidate driver genes and opportunities for precision oncology.

Tumor genomic profiling is increasingly seen as a prerequisite to guide the treatment of patients with cancer. To explore the value of whole-genome sequencing (WGS) in broadening the scope of cancers potentially amenable to a precision therapy, we analysed whole-genome sequencing data on 10,478 patients spanning 35 cancer types recruited to the UK 100,000 Genomes Project. We identified 330 candidate driver genes, including 74 that are new to any cancer. We estimate that approximately 55% of patients studied harbor at least one clinically relevant mutation, predicting either sensitivity or resistance to certain treatments or clinical trial eligibility. By performing computational chemogenomic analysis of cancer mutations we identify additional targets for compounds that represent attractive candidates for future clinical trials. This study represents one of the most comprehensive efforts thus far to identify cancer driver genes in the real world setting and assess their impact on informing precision oncology.

Genetic landscape of interval and screen detected breast cancer.

Interval breast cancers (IBCs) are cancers diagnosed between screening episodes. Understanding the biological differences between IBCs and screen-detected breast-cancers (SDBCs) has the potential to improve mammographic screening and patient management. We analysed and compared the genomic landscape of 288 IBCs and 473 SDBCs by whole genome sequencing of paired tumour-normal patient samples collected as part of the UK 100,000 Genomes Project. Compared to SDBCs, IBCs were more likely to be lobular, higher grade, and triple negative. A more aggressive clinical phenotype was reflected in IBCs displaying features of genomic instability including a higher mutation rate and number of chromosomal structural abnormalities, defective homologous recombination and TP53 mutations. We did not however, find evidence to indicate that IBCs are associated with a significantly different immune response. While IBCs do not represent a unique molecular class of invasive breast cancer they exhibit a more aggressive phenotype, which is likely to be a consequence of the timing of tumour initiation. This information is relevant both with respect to treatment as well as informing the screening interval for mammography.

Radiogenomic biomarkers for immunotherapy in glioblastoma: A systematic review of magnetic resonance imaging studies.

Background: Immunotherapy is an effective "precision medicine" treatment for several cancers. Imaging signatures of the underlying genome (radiogenomics) in glioblastoma patients may serve as preoperative biomarkers of the tumor-host immune apparatus. Validated biomarkers would have the potential to stratify patients during immunotherapy clinical trials, and if trials are beneficial, facilitate personalized neo-adjuvant treatment. The increased use of whole genome sequencing data, and the advances in bioinformatics and machine learning make such developments plausible. We performed a systematic review to determine the extent of development and validation of immune-related radiogenomic biomarkers for glioblastoma. Methods: A systematic review was performed following PRISMA guidelines using the PubMed, Medline, and Embase databases. Qualitative analysis was performed by incorporating the QUADAS 2 tool and CLAIM checklist. PROSPERO registered: CRD42022340968. Extracted data were insufficiently homogenous to perform a meta-analysis. Results: Nine studies, all retrospective, were included. Biomarkers extracted from magnetic resonance imaging volumes of interest included apparent diffusion coefficient values, relative cerebral blood volume values, and image-derived features. These biomarkers correlated with genomic markers from tumor cells or immune cells or with patient survival. The majority of studies had a high risk of bias and applicability concerns regarding the index test performed. Conclusions: Radiogenomic immune biomarkers have the potential to provide early treatment options to patients with glioblastoma. Targeted immunotherapy, stratified by these biomarkers, has the potential to allow individualized neo-adjuvant precision treatment options in clinical trials. However, there are no prospective studies validating these biomarkers, and interpretation is limited due to study bias with little evidence of generalizability.

Whole genome sequencing refines stratification and therapy of patients with clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, but a comprehensive description of its genomic landscape is lacking. We report the whole genome sequencing of 778 ccRCC patients enrolled in the 100,000 Genomes Project, providing the most detailed somatic mutational landscape to date. We identify new driver genes, which as well as emphasising the major role of epigenetic regulation in ccRCC highlight additional biological pathways extending opportunities for drug repurposing. Genomic characterisation identified patients with divergent clinical outcome; higher number of structural copy number alterations associated with poorer prognosis, whereas VHL mutations were independently associated with a better prognosis. The twin observations that higher T-cell infiltration is associated with better outcome and that genetically predicted immune evasion is not common supports the rationale for immunotherapy. These findings should inform personalised surveillance and treatment strategies for ccRCC patients.

Therapeutic Targeting of Glioblastoma and the Interactions with Its Microenvironment.

Glioblastoma (GBM) is the most common primary malignant brain tumour, and it confers a dismal prognosis despite intensive multimodal treatments. Whilst historically, research has focussed on the evolution of GBM tumour cells themselves, there is growing recognition of the importance of studying the tumour microenvironment (TME). Improved characterisation of the interaction between GBM cells and the TME has led to a better understanding of therapeutic resistance and the identification of potential targets to block these escape mechanisms. This review describes the network of cells within the TME and proposes treatment strategies for simultaneously targeting GBM cells, the surrounding immune cells, and the crosstalk between them.

Whole-genome sequencing of chronic lymphocytic leukemia identifies subgroups with distinct biological and clinical features.

The value of genome-wide over targeted driver analyses for predicting clinical outcomes of cancer patients is debated. Here, we report the whole-genome sequencing of 485 chronic lymphocytic leukemia patients enrolled in clinical trials as part of the United Kingdom's 100,000 Genomes Project. We identify an extended catalog of recurrent coding and noncoding genetic mutations that represents a source for future studies and provide the most complete high-resolution map of structural variants, copy number changes and global genome features including telomere length, mutational signatures and genomic complexity. We demonstrate the relationship of these features with clinical outcome and show that integration of 186 distinct recurrent genomic alterations defines five genomic subgroups that associate with response to therapy, refining conventional outcome prediction. While requiring independent validation, our findings highlight the potential of whole-genome sequencing to inform future risk stratification in chronic lymphocytic leukemia.

Germline MBD4 deficiency causes a multi-tumor predisposition syndrome.

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.

Relationship between genetically determined telomere length and glioma risk.

BACKGROUND: Telomere maintenance is increasingly recognized as being fundamental to glioma oncogenesis with longer leukocyte telomere length (LTL) reported to increase risk of glioma. To gain further insight into the relationship between telomere genetics and risk of glioma, we conducted several complementary analyses, using genome-wide association studies data on LTL (78 592 individuals) and glioma (12 488 cases and 18 169 controls). METHODS: We performed both classical and summary Mendelian randomization (SMR), coupled with heterogeneity in dependent instruments tests, at genome-wide significant LTL loci to examine if an association was mediated by the same causal variant in glioma. To prioritize genes underscoring glioma-LTL associations, we analyzed gene expression and DNA methylation data. RESULTS: Genetically increased LTL was significantly associated with increased glioma risk, random-effects inverse variance weighted ORs per 1 SD unit increase in the putative risk factor (odds ratio [OR]SD) 4.79 (95% confidence interval: 2.11-10.85; P = 1.76 × 10-4). SMR confirmed the previously reported LTL associations at 3q26.2 (TERC; PSMR = 1.33 × 10-5), 5p15.33 (TERT; PSMR = 9.80 × 10-27), 10q24.33 (STN1 alias OBFC1; PSMR = 4.31 × 10-5), and 20q13.3 (STMN3/RTEL1; PSMR = 2.47 × 10-4) glioma risk loci. Our analysis implicates variation at 1q42.12 (PSMR = 1.55 × 10-2), 6p21.3 (PSMR = 9.76 × 10-3), 6p22.2 (PSMR = 5.45 × 10-3), 7q31.33 (PSMR = 6.52 × 10-3), and 11q22.3 (PSMR = 8.89 × 10-4) as risk factors for glioma risk. While complicated by patterns of linkage disequilibrium, genetic variation involving PARP1, PRRC2A, CARMIL1, POT1, and ATM-NPAT1 was implicated in the etiology of glioma. CONCLUSIONS: These observations extend the role of telomere-related genes in the development of glioma.

Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes.

To obtain a comprehensive picture of composite genetic driver events and clonal dynamics in subtypes of paediatric acute lymphoblastic leukaemia (ALL) we analysed tumour-normal whole genome sequencing and expression data from 361 newly diagnosed patients. We report the identification of both structural drivers, as well as recurrent non-coding variation in promoters. Additionally we found the transcriptional profile of histone gene cluster 1 and CTCF altered tumours shared hallmarks of hyperdiploid ALL suggesting a 'hyperdiploid like' subtype. ALL subtypes are driven by distinct mutational processes with AID mutagenesis being confined to ETV6-RUNX1 tumours. Subclonality is a ubiquitous feature of ALL, consistent with Darwinian evolution driving selection and expansion of tumours. Driver mutations in B-cell developmental genes (IKZF1, PAX5, ZEB2) tend to be clonal and RAS/RTK mutations subclonal. In addition to identifying new avenues for therapeutic exploitation, this analysis highlights that targeted therapies should take into account composite mutational profile and clonality.

Cumulative incidence and risk factors for radiation induced leukoencephalopathy in high grade glioma long term survivors.

The incidence and risk factors associated with radiation-induced leukoencephalopathy (RIL) in long-term survivors of high-grade glioma (HGG) are still poorly investigated. We performed a retrospective research in our institutional database for patients with supratentorial HGG treated with focal radiotherapy, having a progression-free overall survival > 30 months and available germline DNA. We reviewed MRI scans for signs of leukoencephalopathy on T2/FLAIR sequences, and medical records for information on cerebrovascular risk factors and neurological symptoms. We investigated a panel of candidate single nucleotide polymorphisms (SNPs) to assess genetic risk. Eighty-one HGG patients (18 grade IV and 63 grade III, 50M/31F) were included in the study. The median age at the time of radiotherapy was 48 years old (range 18-69). The median follow-up after the completion of radiotherapy was 79 months. A total of 44 patients (44/81, 54.3%) developed RIL during follow-up. Twenty-nine of the 44 patients developed consistent symptoms such as subcortical dementia (n = 28), gait disturbances (n = 12), and urinary incontinence (n = 9). The cumulative incidence of RIL was 21% at 12 months, 42% at 36 months, and 48% at 60 months. Age > 60 years, smoking, and the germline SNP rs2120825 (PPARg locus) were associated with an increased risk of RIL. Our study identified potential risk factors for the development of RIL (age, smoking, and the germline SNP rs2120825) and established the rationale for testing PPARg agonists in the prevention and management of late-delayed radiation-induced neurotoxicity.

Partitioned glioma heritability shows subtype-specific enrichment in immune cells.

BACKGROUND: Epidemiological studies of adult glioma have identified genetic syndromes and 25 heritable risk loci that modify individual risk for glioma, as well increased risk in association with exposure to ionizing radiation and decreased risk in association with allergies. In this analysis, we assess whether there is a shared genome-wide genetic architecture between glioma and atopic/autoimmune diseases. METHODS: Using summary statistics from a glioma genome-wide association studies (GWAS) meta-analysis, we identified significant enrichment for risk variants associated with gene expression changes in immune cell populations. We also estimated genetic correlations between glioma and autoimmune, atopic, and hematologic traits using linkage disequilibrium score regression (LDSC), which leverages genome-wide single-nucleotide polymorphism (SNP) associations and patterns of linkage disequilibrium. RESULTS: Nominally significant negative correlations were observed for glioblastoma (GB) and primary biliary cirrhosis (rg = -0.26, P = .0228), and for non-GB gliomas and celiac disease (rg = -0.32, P = .0109). Our analyses implicate dendritic cells (GB pHM = 0.0306 and non-GB pHM = 0.0186) in mediating both GB and non-GB genetic predisposition, with GB-specific associations identified in natural killer (NK) cells (pHM = 0.0201) and stem cells (pHM = 0.0265). CONCLUSIONS: This analysis identifies putative new associations between glioma and autoimmune conditions with genomic architecture that is inversely correlated with that of glioma and that T cells, NK cells, and myeloid cells are involved in mediating glioma predisposition. This provides further evidence that increased activation of the acquired immune system may modify individual susceptibility to glioma.

Searching for causal relationships of glioma: a phenome-wide Mendelian randomisation study.

BACKGROUND: The aetiology of glioma is poorly understood. Summary data from genome-wide association studies (GWAS) can be used in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to search for glioma risk factors. METHODS: We performed an MR-PheWAS analysing 316 phenotypes, proxied by 8387 genetic variants, and summary genetic data from a GWAS of 12,488 glioma cases and 18,169 controls. Causal effects were estimated under a random-effects inverse-variance-weighted (IVW-RE) model, with robust adjusted profile score (MR-RAPS), weighted median and mode-based estimates computed to assess the robustness of findings. Odds ratios per one standard deviation increase in each phenotype were calculated for all glioma, glioblastoma (GBM) and non-GBM tumours. RESULTS: No significant associations (P < 1.58 × 10-4) were observed between phenotypes and glioma under the IVW-RE model. Suggestive associations (1.58 × 10-4 < P < 0.05) were observed between leukocyte telomere length (LTL) with all glioma (ORSD = 3.91, P = 9.24 × 10-3) and GBM (ORSD = 4.86, P = 3.23 × 10-2), but the association was primarily driven by the TERT variant rs2736100. Serum low-density lipoprotein cholesterol and plasma HbA1C showed suggestive associations with glioma (ORSD = 1.11, P = 1.39 × 10-2 and ORSD = 1.28, P = 1.73 × 10-2, respectively), both associations being reliant on single genetic variants. CONCLUSIONS: Our study provides further insight into the aetiological basis of glioma for which published data have been mixed.

An enhanced genetic model of relapsed IGH-translocated multiple myeloma evolutionary dynamics.

Most patients with multiple myeloma (MM) die from progressive disease after relapse. To advance our understanding of MM evolution mechanisms, we performed whole-genome sequencing of 80 IGH-translocated tumour-normal newly diagnosed pairs and 24 matched relapsed tumours from the Myeloma XI trial. We identify multiple events as potentially important for survival and therapy-resistance at relapse including driver point mutations (e.g., TET2), translocations (MAP3K14), lengthened telomeres, and increased genomic instability (e.g., 17p deletions). Despite heterogeneous mutational processes contributing to relapsed mutations across MM subtypes, increased AID/APOBEC activity is particularly associated with shorter progression time to relapse, and contributes to higher mutational burden at relapse. In addition, we identify three enhanced major clonal evolution patterns of MM relapse, independent of treatment strategies and molecular karyotypes, questioning the viability of "evolutionary herding" approach in treating drug-resistant MM. Our data show that MM relapse is associated with acquisition of new mutations and clonal selection, and suggest APOBEC enzymes among potential targets for therapy-resistant MM.

Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.

Search for multiple myeloma risk factors using Mendelian randomization.

The etiology of multiple myeloma (MM) is poorly understood. Summary data from genome-wide association studies (GWASs) of multiple phenotypes can be exploited in a Mendelian randomization (MR) phenome-wide association study (PheWAS) to search for factors influencing MM risk. We performed an MR-PheWAS analyzing 249 phenotypes, proxied by 10 225 genetic variants, and summary genetic data from a GWAS of 7717 MM cases and 29 304 controls. Odds ratios (ORs) per 1 standard deviation increase in each phenotype were estimated under an inverse variance weighted random effects model. A Bonferroni-corrected threshold of P = 2 × 10-4 was considered significant, whereas P < .05 was considered suggestive of an association. Although no significant associations with MM risk were observed among the 249 phenotypes, 28 phenotypes showed evidence suggestive of association, including increased levels of serum vitamin B6 and blood carnitine (P = 1.1 × 10-3) with greater MM risk and ω-3 fatty acids (P = 5.4 × 10-4) with reduced MM risk. A suggestive association between increased telomere length and reduced MM risk was also noted; however, this association was primarily driven by the previously identified risk variant rs10936599 at 3q26 (TERC). Although not statistically significant, increased body mass index was associated with increased risk (OR, 1.10; 95% confidence interval, 0.99-1.22), supporting findings from a previous meta-analysis of prospective observational studies. Our study did not provide evidence supporting any modifiable factors examined as having a major influence on MM risk; however, it provides insight into factors for which the evidence has previously been mixed.

Algorithmic considerations when analysing capture Hi-C data.

Chromosome conformation capture methodologies have provided insight into the effect of 3D genomic architecture on gene regulation. Capture Hi-C (CHi-C) is a recent extension of Hi-C that improves the effective resolution of chromatin interactions by enriching for defined regions of biological relevance. The varying targeting efficiency between capture regions, however, introduces bias not present in conventional Hi-C, making analysis more complicated. Here we consider salient features of an algorithm that should be considered in evaluating the performance of a program used to analyse CHi-C data in order to infer meaningful interactions. We use the program CHICAGO to analyse promotor capture Hi-C data generated on 28 different cell lines as a case study.

Lack of association between modifiable exposures and glioma risk: a Mendelian randomization analysis.

BACKGROUND: The etiological basis of glioma is poorly understood. We have used genetic markers in a Mendelian randomization (MR) framework to examine if lifestyle, cardiometabolic, and inflammatory factors influence the risk of glioma. This methodology reduces bias from confounding and is not affected by reverse causation. METHODS: We identified genetic instruments for 37 potentially modifiable risk factors and evaluated their association with glioma risk using data from a genome-wide association study of 12 488 glioma patients and 18 169 controls. We used the estimated odds ratio of glioma associated with each of the genetically defined traits to infer evidence for a causal relationship with the following exposures:Lifestyle and dietary factors-height, plasma insulin-like growth factor 1, blood carnitine, blood methionine, blood selenium, blood zinc, circulating adiponectin, circulating carotenoids, iron status, serum calcium, vitamins (A1, B12, B6, E, and 25-hydroxyvitamin D), fatty acid levels (monounsaturated, omega-3, and omega-6) and circulating fetuin-A;Cardiometabolic factors-birth weight, high density lipoprotein cholesterol, low density lipoprotein cholesterol, total cholesterol, total triglycerides, basal metabolic rate, body fat percentage, body mass index, fasting glucose, fasting proinsulin, glycated hemoglobin levels, diastolic and systolic blood pressure, waist circumference, waist-to-hip ratio; andInflammatory factors- C-reactive protein, plasma interleukin-6 receptor subunit alpha and serum immunoglobulin E. RESULTS: After correction for the testing of multiple potential risk factors and excluding associations driven by one single nucleotide polymorphism, no significant association with glioma risk was observed (ie, PCorrected > 0.05). CONCLUSIONS: This study did not provide evidence supporting any of the 37 factors examined as having a significant influence on glioma risk.

Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk.

There is increasing evidence for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children. To identify new risk variants for B-cell ALL (B-ALL) we conducted a meta-analysis with four GWAS (genome-wide association studies), totalling 5321 cases and 16,666 controls of European descent. We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P = 2.11 × 10-8), for high-hyperdiploid ALL at 5q31.1 (rs886285, P = 1.56 × 10-8) and 6p21.31 (rs210143 in BAK1, P = 2.21 × 10-8), and ETV6-RUNX1 ALL at 17q21.32 (rs10853104 in IGF2BP1, P = 1.82 × 10-8). Particularly notable are the pleiotropic effects of the BAK1 variant on multiple haematological malignancies and specific effects of IGF2BP1 on ETV6-RUNX1 ALL evidenced by both germline and somatic genomic analyses. Integration of GWAS signals with transcriptomic/epigenomic profiling and 3D chromatin interaction data for these leukaemia risk loci suggests deregulation of B-cell development and the cell cycle as central mechanisms governing genetic susceptibility to ALL.

Genetic predisposition to mosaic Y chromosome loss in blood.

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.

Transcriptome-wide association study of multiple myeloma identifies candidate susceptibility genes.

BACKGROUND: While genome-wide association studies (GWAS) of multiple myeloma (MM) have identified variants at 23 regions influencing risk, the genes underlying these associations are largely unknown. To identify candidate causal genes at these regions and search for novel risk regions, we performed a multi-tissue transcriptome-wide association study (TWAS). RESULTS: GWAS data on 7319 MM cases and 234,385 controls was integrated with Genotype-Tissue Expression Project (GTEx) data assayed in 48 tissues (sample sizes, N = 80-491), including lymphocyte cell lines and whole blood, to predict gene expression. We identified 108 genes at 13 independent regions associated with MM risk, all of which were in 1 Mb of known MM GWAS risk variants. Of these, 94 genes, located in eight regions, had not previously been considered as a candidate gene for that locus. CONCLUSIONS: Our findings highlight the value of leveraging expression data from multiple tissues to identify candidate genes responsible for GWAS associations which provide insight into MM tumorigenesis. Among the genes identified, a number have plausible roles in MM biology, notably APOBEC3C, APOBEC3H, APOBEC3D, APOBEC3F, APOBEC3G, or have been previously implicated in other malignancies. The genes identified in this TWAS can be explored for follow-up and validation to further understand their role in MM biology.